The reader should note that this is not meant to be a comprehensive, perfectly reasoned review of all available evidence, which could easily stretch into the hundreds of pages depending on the level of detail demanded. Topics will be covered to the arbitrary level of depth which I personally judge to be appropriate; if felt inadequate, the reader may perform their own research, hopefully using the citations in this post as a useful springboard. Ultimately, if we want to apply this research to our own lives, we must accept some degree of inherent uncertainty, which the structure of this post intentionally reflects.<\/p>\n\n\n\n
Disclaimer: This web site is provided for educational and informational purposes only and does not constitute providing medical advice or professional services. The information provided should not be used for diagnosing or treating a health problem or disease, and those seeking personal medical advice should consult with a licensed physician. <\/em><\/p>\n\n\n\n General approach<\/strong><\/p>\n\n\n\n Let’s think a little bit about what the best piece of evidence for a given “anti-aging” treatment would be. In an ideal world, we would have evidence from multiple randomized interventional studies performed on large, representative, healthy human samples that independently demonstrate reproducible lifespan extension and delay of average onset for multiple age-related diseases. Obviously, if any such evidence existed for some compound, we would all know about it, and most of us would already be taking it; needless to say, there is no intervention whatsoever for which this level of evidence exists, even for interventions that “we all know” are good for us, like routine exercise.<\/p>\n\n\n\n We can weaken this requirement in two primary ways. First, we can accept evidence from nonhumans, allowing us to consider evidence generated from model organisms such as mice, C. elegans,<\/em> and yeast. Such research may not translate cleanly to humans (if at all), but it stands to reason that there must exist mechanisms for extending lifespan which are conserved across species. Second, we can accept noninterventional human evidence, sacrificing some ability to determine causality but allowing us to combine compelling cross-sectional data with theoretical understanding of plausible anti-aging mechanisms. We will see that the most interesting therapeutics by and large tend to fall into one of these two categories.<\/p>\n\n\n\n Not all evidence is created equal. A core principle of my process of evaluation is that well over 50% of modern biological research is literally fake (fabricated from whole cloth), essentially fake (p<\/em>-hacked or otherwise selectively presented), or so incompetently executed as to be pure noise. Additionally, entire fields of research are contaminated by severe financial conflicts of interest, and all academic research is governed by incentive structures hardly conducive to determination of absolute truth. Unfortunately, we only live once, and it is much easier to harm a complex physiological system than to improve it, so it seems prudent to apply a fairly conservative filter on the set of interventions that we choose to apply to our own bodies.<\/p>\n\n\n\n Additionally, concerns about drug-drug interactions, as well as the fact that known interventions likely target overlapping mechanisms (leading to rapidly diminishing returns if treatments are not carefully selected), are strong motivations to only consider the strongest bodies of evidence rather than adopting a “bucket list” approach. It is better to properly target a small number of known mechanisms in the safest ways possible using highly specific drugs than to take a hundred supplements, each with weak but pleiotropic effects and unknown absorption profiles, and hope that a good outcome is somehow achieved.<\/p>\n\n\n\n Overall, we are faced with a problem of considerable difficulty. Nevertheless, I believe that we now understand enough about human physiology and the effects of various drugs that a number of actionable recommendations can be produced from the mists of biomedical research. Let’s take a look.<\/p>\n\n\n\n Evidence from model organisms: the NIA ITP<\/strong><\/p>\n\n\n\n Among model organisms, the most well-understood mammal is surely the mouse, and the gold standard for lifespan extension in mice is the National Institute of Aging’s Interventions Testing Program (ITP).<\/a> This program tests a small number of drugs in large, well-controlled, multi-center studies to see if they extend the lifespan of genetically heterogeneous mice. <\/p>\n\n\n\n Several characteristics of the ITP are highly appealing. It uses a high sample size and experiments are well-powered to detect differences in lifespan; it actually measures total mouse lifespan, the most robust endpoint conceivable and one for which differences have the highest probability of translating to other species; it is a multi-center study performed in standardized conditions where control mice are not subject to artificially adverse environments; treatments are preregistered so results are not p<\/em>-hacked; finally, the mice used are all from the standardized UM-HET3 four-way cross which do not have the genetic peculiarities of the vastly more common and severely inbred C57BL\/6 strain. In short, it is a good experiment. On top of this, the ITP is an expensive program, so the set of compounds tested is selected based on the strength of preexisting evidence, meaning that there is typically a large body of supporting literature to corroborate positive results.<\/p>\n\n\n\n It is not uncommon for interventions to show lifespan extension in a lower-quality mouse study and to then fail to replicate in the ITP. The reasons why vary, but typically this is because a highly inbred strain is used in preliminary studies or because the mice are not housed properly (control group shows depressed lifespan); in both cases, the treatment is essentially fixing something that is deeply broken, rather than showing a benefit on top of a healthy baseline. For example, one might think that Dang et al.<\/em> (2019)<\/a> supplies intriguing evidence for pro-longevity effects of berberine, until one notices that the median lifespan in both control and treatment groups are below 700 days. We know that properly cared for C57BL\/6 mice have a median lifespan of ~850 days,<\/a> suggesting that the effects of berberine may not replicate in the context of a less dysfunctional colony.<\/p>\n\n\n\n If we want to choose treatments with the strongest evidence in model organisms, then, a logical place to look is at the ITP’s experimental results.<\/a> In rough order of most to least replication within the ITP itself, the following compounds have been shown to extend both median and maximum lifespan: rapamycin, acarbose, canagliflozin, 17\u03b1-estradiol (males), and glycine (males only; weak effect), as well as various combinations thereof. (Metformin also extended lifespan, but only in combination with rapamycin; this is discussed further in a subsequent section.) The evidence for rapamycin is especially strong, with clear extension of lifespan by 20% or more across different starting ages and treatment regimes, suggesting that it is one of our strongest candidates for lifespan-extending treatments.<\/p>\n\n\n\n The case for rapamycin<\/strong><\/p>\n\n\n\n The literature on rapamycin and its ability to extend lifespan at the correct dosages is extensive, so we will only briefly touch on its history here; much more detail is given in the magisterial review by Mannick and Lamming (2023).<\/a> Briefly, genetic inhibition of the mTORC1 kinase was found more than two decades ago to extend the lifespan of multiple model organisms, a result which was then replicated many times over with rapamycin, an orally available inhibitor of mTORC1. At high doses, rapamycin is used as a potent immunosuppressant that prevents post-transplant rejection; however, evidence from animal models suggests that intermittent or low-dose treatment prolongs lifespan without exposure to undesirable side effects, such as total immunosuppression, hyperlipidemia, or hyperglycemia.<\/p>\n\n\n\n Rapamycin treatment seems to extend lifespan under a variety of different conditions. For example, Miller et al.<\/em> (2014)<\/a> and Miller et al.<\/em> (2010)<\/a> also report that the greatest rapamycin-dependent lifespan extension in the ITP is seen with treatment starting at 9 months of age in mice (equivalent to a 30-year-old human), with 23% extension in males and 26% in females:<\/p>\n\n\n However, even when treatment was started in extremely old age (Harrison et al.<\/em> (2009))<\/a>, rapamycin extended lifespan by 9% in males and 14% in females:<\/p>\n\n\n A starting age of 600 days in mice corresponds to approximately 60 years of age in humans, suggesting that a substantial benefit can be seen even if treatment is not started until one’s later years. (Note that the above graph demonstrates an artefactual separation of the survival curve for male mice even before the 600-day mark; the authors attribute this to unusual conditions at one or two specific study sites.)<\/p>\n\n\n\n Effects are also detected across varying treatment regimes, e.g.<\/em> single dose vs. intermittent vs. continual administration (see for example Bitto et al.<\/em> (2016)<\/a> on transient usage in middle-aged mice), and rapamycin’s ability to extend lifespan is additive when combined with mechanistically distinct drugs like acarbose. Overall, the robustness of these results suggest that the beneficial effects of rapamycin have a relatively higher likelihood of translating to humans.<\/p>\n\n\n\n The fact that rapamycin is clinically used (at very high doses, achieving serum concentrations much greater than those of the mice in the studies above) as an immunosuppressant means that a priori,<\/em> the most concerning potential side effect of rapamycin treatment, even at lower doses, is undesirable immune suppression. Curiously, however, limited evidence from human trials suggests that mTORC1 inhibition in the elderly can actually improve<\/em> immune function:<\/p>\n\n\n\n While these studies did not use rapamycin itself, they supply compelling evidence that mTORC1 inhibition in the elderly can actually boost overall immune response (perhaps by reducing systemic inflammation that dampens the immune system), and indirectly suggest that when appropriately dosed, rapamycin should be relatively well tolerated in healthy adults.<\/p>\n\n\n\n A recent survey of off-label rapamycin usage by Kaeberlein et al.<\/em> (2023)<\/a> also suggests that the safety profile of rapamycin is fairly benign. While the data are purely observational and uncontrolled, it is still notable that the only adverse event that was significantly more prevalent in users of rapamycin was the formation of canker sores (mouth ulcerations), at a rate of 14.7% compared to 4.7% in the non-user group. While canker sores are a known side effect of sirolimus usage, they are relatively benign and self-resolving, and generally not considered to be a harbinger of broader, underlying autoimmune dysfunction in the same manner as other autoimmune disorders. Additionally, the self-reported weekly dosages of rapamycin are quite variable, and it is unknown to what extent the prevalence of canker sores varied with dosage.<\/p>\n\n\n\n Another way to consider plausible adverse side effects is to consider the beneficial effects of mTOR activation. Notably, it is well known (Watson and Baar (2014)<\/a>) that the beneficial anabolic effects of exercise are mediated through mTOR signaling, and so a reasonable concern is that continued rapamycin usage would cause a reduction in muscular or skeletal mass. Physical frailty is a significant contributor to mortality and reduced quality of life in the elderly (Li et al.<\/em> (2018)<\/a>), so it is plausible that such effects, if present, could entirely counteract any beneficial effects of rapamycin. Thankfully, this does not seem to be the case: at low and intermittent doses, rapamycin in fact seems to protect against age-related loss of muscle and bone mass (see Wu et al.<\/em> (2019)<\/a>, Orenduff et al.<\/em> (2022)<\/a>, and many others).<\/p>\n\n\n\n Finally, a recent report by Artoni, Gr\u00fctzmacher, and Demetriades (2022)<\/a> shows that rapamycin is a very “clean” drug, with very few off-target effects beyond inhibition of the mTORC complex at physiologically relevant doses. In general, off-target effects are a major source of specific toxicities; therefore, their absence suggests that there are very few “unknown unknowns” in rapamycin’s safety profile.<\/p>\n\n\n\n Looking beyond potential adverse effects, rapamycin also seems to demonstrate pleiotropic benefits in a number of disparate physiological systems in a manner consistent with a broad “anti-aging” effect:<\/p>\n\n\n\n The papers supplied here only constitute a small fraction of the available literature, all of which consistently points to the benefits of rapamycin treatment on multiple organ systems.<\/p>\n\n\n\n Importantly, the reader should take careful note here of the “flow” of our analysis. We began with the most challenging endpoint possible (extension of median and maximal lifespan) in a very rigorous, well-controlled study (the NIA ITP), checked that rapamycin performed well in that setting, then only afterward<\/em> began considering individual, smaller, less well-controlled studies of alternate endpoints like muscle mass and hearing loss. The fact that we robustly observe a large absolute quantity of lifespan extension, which requires<\/em> the benefits of rapamycin benefits to accrue systemically, significantly increases our credence in the weaker literature, which in the absence of that strong lifespan data is much more likely to be artifactual or p<\/em>-hacked. In contrast, if we saw a number of different papers reporting benefits across multiple organ systems but eventually failed to notice any effect on lifespan in a rigorous study, that would suggest that the individual studies are themselves flawed, because an intervention that has a real effect on multiple aging phenotypes should (if real) be expected to extend total lifespan.<\/p>\n\n\n\n Overall, my own conclusion is that rapamycin has a risk-reward profile favorable enough that individuals, certainly those in middle or later age, and perhaps even those in early adulthood, should consider experimenting with a schedule of rapamycin supplementation. (Exact dosing details will be discussed in a later section.) Such a regimen is certainly not without risks, but it may also come with considerable benefits.<\/p>\n\n\n\n Comparing rapamycin to fasting<\/strong><\/p>\n\n\n\n When trying to decide whether or not the risks of rapamycin are worth the potential upside, it’s useful to take a step back and consider the recent popularity of dietary interventions such as ketosis or intermittent fasting. A number of publications in the late 2010s (reviewed in de Cabo and Mattson (2019)<\/a>) spurred substantial and enduring popular interest in time-restricted and\/or compositionally-restricted dieting; either you have experimented with them yourself, or you are likely familiar with someone who has. Implicitly, people seem to accept that the risk-reward profiles of fasting, etc.<\/em> are within the acceptable range.<\/p>\n\n\n\n However, these dietary interventions are themselves not particularly safe to begin with! A comprehensive review by Lee et al.<\/em> (2021)<\/a> notes that “anti-aging diets\u201c such as caloric restriction or intermittent fasting are often found to decrease<\/em> lifespan in up to one-third of genetic backgrounds or to have directionally opposite effects on longevity in males vs. females. Severe dietary restrictions also come with their own specific problems: adherence is very challenging, alteration of dietary patterns impacts overall quality of life, and protein-deficient diets may even increase<\/em> rather than decrease mortality in sufficiently aged populations (Levine et al.<\/em> (2014)<\/a>). Dieting also very obviously exposes people to risk of “adverse events” in the form of lower energy levels, dampened immune responses, grogginess, and mood alterations; however, because the nature of the intervention is behavioral rather than pharmaceutical, we do not typically consider these “risks” as properly as we should. Finally, part of the benefits of fasting are thought to originate from mTOR inhibition, suggesting that rapamycin administration could realize those beneficial effects with a much lower risk profile.<\/p>\n\n\n\n These lines of reasoning suggest that if<\/em> we are willing to accept that intermittent fasting is potentially worth sustaining throughout your lifespan, then it is at least very plausible that taking rapamycin in some form, to cleanly achieve the benefits of transient mTOR inhibition without the numerous, “dirty” side effects of fasting, is a strictly superior option. Furthermore, conditional on already taking rapamycin,<\/em> it is unclear that the marginal<\/em> benefit of fasting is positive at all, i.e.,<\/em> taking into account the benefits of rapamycin itself, one should probably eat normally rather than bother with unusual dietary modifications.<\/p>\n\n\n\n The above discussion is inherently somewhat “sketchy” in nature, in the sense that there is little hard data to go off here, and we must rely on a good dose of analogical and first-principles reasoning. Unfortunately, when it comes to making practical decisions about lifespan extension, this sort of situation is the norm, and the wealth of data available to us on rapamycin treatment is by far the exception. One should note that there is a major exception to the above which comes to mind: in the case where an individual is prone to weight gain or already overweight, dietary interventions such as intermittent fasting or ketosis can make it easier to lose weight from a behavioral standpoint,<\/em> and the health benefits of losing excess weight are likely so overwhelmingly great that the risk of adverse effects are inconsequential by comparison. In such a situation, then, one might consider taking rapamycin for its anti-obesogenic effects (Bitto et al.<\/em> (2021)<\/a>) as well as experimenting with different dietary patterns to see which one enables the most rapid weight loss.<\/p>\n\n\n\n Reduction of postprandial glucose spikes<\/strong><\/p>\n\n\n\n Moving on from rapamycin, one immediately notices that several different promising interventions seem to fall under the broad class of pharmaceuticals that reduce postprandial (i.e.,<\/em> after eating a meal) glucose spikes:<\/p>\n\n\n\n Several observations point toward a common mechanism underlying these results from different drug regimens. All of these treatments are known to lower glucose levels in general, and they are typically used for this purpose to manage diabetes mellitus; however, the dosages of acarbose and canagliflozin used by the ITP are not known to lower hemoglobin A1C levels (a time-averaged measure of blood glucose levels over the past three months), suggesting that they act through dampening or smoothing glucose spikes rather than through reduction of total integrated glucose levels over time. The consistency of sexual dimorphism in the drugs’ effects on total longevity (if any effect is observed at all) is also suggestive of a a shared mechanistic basis.<\/p>\n\n\n\n Reduction of postprandial glucose spikes also seems to act through mechanisms which are largely distinct from mTORC inhibition, as shown in a recent study by Strong et al.<\/em> (2022)<\/a> who find additive beneficial effects from a combination of rapamycin and acarbose. Such treatments may therefore have high marginal value even for people who are already taking rapamycin.<\/p>\n\n\n\n However, from a purely practical perspective, acarbose and canagliflozin have a number of undesirable safety properties. For example, acarbose is known to induce diarrhea, and canagliflozin (along with comparable SGLT2 inhibitors) increases frequency of urination and genital tract infections. Anecdotally, subjects report<\/a> that these side effects are not as severe when their diet composition includes fewer simple carbs, although this behavioral modification itself likely reduces the beneficial effects of these drugs via dampening postprandial glucose spikes, hence reducing the value proposition of the whole endeavor. Additionally, even a single incidence of untimely diarrhea or UTI contraction may easily lead to permanent cessation of drug treatment. Broadly speaking, I would find it difficult to recommend acarbose or SGLT2 inhibitors like canagliflozin for daily use.<\/p>\n\n\n\n That does not mean that this line of inquiry does not have insights to offer us! Thankfully, if it is in fact true that reduction of postprandial glucose spikes has a tremendous benefit to overall longevity, we can simply examine what the enormous literature on management of diabetes mellitus and glycemic load has to teach us:<\/p>\n\n\n\n It is certainly possible that acarbose, canagliflozin, etc.<\/em> also operate through alternate mechanisms which would not be captured by the above lifestyle or dietary interventions. However, the most parsimonious explanation for the results observed thus far is that reduction of peak postprandial glucose levels extends lifespan and slows the onset of age-related disease, especially (but not exclusively) in males. Given that fiber supplementation is extremely cheap and has essentially zero risk of adverse side effects, consumption of large amounts of soluble fiber at morning (as much as 10 g or more if tolerable) is nearly self-recommending. (Note that taking fiber alongside other medications is likely undesirable due to its ability to affect drug absorption; see e.g. Gonz\u00e1lez Canga et al.<\/em> (2010)<\/a>.) Lifestyle changes such as post-meal exercise, slower mealtimes, and consumption of more complex carbohydrates also seem prudent, although ability to maintain such habits will vary per individual.<\/p>\n\n\n\n Speculation on the mechanism of 17\u03b1-estradiol<\/strong><\/p>\n\n\n\n 17\u03b1-estradiol, also known as a “non-feminizing” stereoisomer of 17\u03b2-estradiol, was first found to extend the median lifespan of male mice by 12% in the ITP by Harrison et al.<\/em> (2014)<\/a>, work which was subsequently reproduced in a future ITP experiment by Harrison et al.<\/em> (2020)<\/a> with similar effect sizes:<\/p>\n\n\n Curiously, while 17\u03b1-estradiol is bioavailable in both male and female mice, it only produces a pro-longevity effect in males, for reasons which remain unclear. Additionally, the greatest extension of median lifespan was observed when starting treatment at 16 months of age (19% improvement), while starting at 20 months of age yielded a considerably smaller benefit (11% improvement). It is therefore somewhat challenging to interpret these results into a clear recommendation for humans. Practical usage of 17\u03b1-estradiol is also frustrated by supply chain issues; it is unclear where to obtain stereochemically pure 17\u03b1-estradiol, how to compound it for oral ingestion, what the pharmacokinetics and pharmacodynamics are in humans, etc.<\/em> Of the interventions which showed success in the NIA ITP, 17\u03b1-estradiol is definitely the most “annoying” to apply in practice.<\/p>\n\n\n\n Can we isolate the mechanistic basis of 17\u03b1-estradiol’s effect on lifespan and perhaps simplify the task before us with that information? A metabolomic study by Garratt et al.<\/em> (2018)<\/a> found that male mice treated with 17\u03b1-estradiol had higher levels of urea cycle intermediates and certain amino acids in the liver, and that these changes disappeared in a cohort of castrated male mice, suggesting that male-specific benefits are mediated through alterations to processes involving male gonadal hormones. This is potentially consistent with the observation that benefits of 17\u03b1-estradiol treatment decline after a certain age, as levels of androgen production are known to decline in elderly males. Additionally, the authors speculate that 17\u03b1-estradiol’s effects are mediated either through metabolites of 17\u03b1-estradiol such as conjugated estriols or, alternatively, through a direct inhibitory effect on 5\u03b1-reductase (5AR) activity, which blocks the conversion of testosterone into dihydrotestosterone (DHT).<\/p>\n\n\n\n If 17\u03b1-estradiol functions through direct association with estrogen receptors or through downstream metabolites such as conjugated estriol, I do not believe that there is sufficient information on safety, dosage, drug supply, etc.<\/em> that lead to practical recommendations for men. However, one possibility does remain open to us, which is that at least some portion of the beneficial effects of 17\u03b1-estradiol treatment act through inhibition of 5\u03b1-reductase and reduction of DHT levels. Its ability to do so is sufficiently potent that it is commercially sold in a topical formulation to treat male pattern baldness through that exact mechanism; furthermore, acting through DHT reduction would be entirely consistent with a dependence on male gonadal hormones, because as males age, their testosterone levels naturally decrease, and since DHT is produced from testosterone, DHT levels also decline.<\/p>\n\n\n\n This observation suggests that we might<\/em> be able to obtain some of the benefits of 17\u03b1-estradiol by taking highly specific 5\u03b1-reductase inhibitors such as finasteride or dutasteride, both of which are commonly used, orally available, inexpensive, and well tolerated drugs with uncommon side effects that generally reverse after cessation of treatment (Hirschburg et al.<\/em> (2016)<\/a>). Given the ease of obtaining finasteride as well as the general lifestyle benefits of preventing male pattern baldness for men, I believe it is easy enough to recommend finasteride (or dutasteride) on the basis of alopecia prevention alone; the addition of even potential<\/em> benefit to longevity via a common mechanism with 17\u03b1-estradiol only further improves the risk-reward tradeoff of 5AR inhibition.<\/p>\n\n\n\n It is likely that in several years’ time, we will understand the mechanisms behind 17\u03b1-estradiol’s extension of murine lifespan sufficiently well to have a clearer idea of how to target the same pathways in humans. For now, my opinion is that the situation is murky enough that it is difficult for me to recommend self-administration of 17\u03b1-estradiol. However, we may at least hope to capture some<\/em> of the benefits of 17\u03b1-estradiol via the far more well-understood finasteride or dutasteride.<\/p>\n\n\n\n Against supplementation of essential amino acids<\/strong><\/p>\n\n\n\n The final and weakest successful intervention in the ITP was glycine, which, when supplemented to UM-HET3 at very high levels (8% of their diet), increased median lifespan of males and females by about 5% (Miller et al.<\/em> (2019)<\/a>). As glycine is a common amino acid and participates in a wide diversity of physiological processes, the underlying mechanism is not fully clear, but this result is consistent with a body of prior research which has found anti-inflammatory effects of glycine supplementation in rodents and humans alike. Coincidentally, Singh et al.<\/em> (2023)<\/a> recently reported that supplementation of taurine (a different amino acid) increased median lifespan of treated mice by over 10%, although such an effect is largely novel and the study was only performed in the highly inbred C57BL\/6 strain. Unfortunately, taurine has not yet been tested in the ITP.<\/p>\n\n\n\n Do these results point at supplementation of certain amino acids as a potential way to extend lifespan of healthy adults? I do not believe so. Feeding mice 8% of their diet in a single amino acid (glycine) is a huge<\/em> dosage which is completely impractical to reproduce in any human setting; the effect sizes seen are quite small and may very well attenuate even further when translated to humans; finally, to the extent that glycine supplementation extends lifespan by antagonizing methionine activation of the mTOR pathway (Kitada et al.<\/em> (2020)<\/a>), the same benefits are already achieved via rapamycin. In the case of taurine, there is but a single, unreplicated study, claiming an almost implausibly high effect size and what is, frankly, almost an excessively clean narrative of anti-aging effects in the absence of much background literature. Additionally, if we accept that glycine’s beneficial effects work through suppression of methionine-based mTOR signaling, we must also consequently accept that there is some generic risk that supplementation of the wrong<\/em> amino acid (like methionine itself) could have an adverse, lifespan-reducing effect.<\/p>\n\n\n\n That brings us to the end of the (very short) list of interventions tested in the ITP which produced clear, robust extension of median and maximal lifespan of at least one sex! The reader, hopefully, can feel, as I do, the strength of supporting evidence declining quite precipitously as we move down the list. If even glycine, which is one of the very few successes of the ITP, does not seem worth using in humans, that suggests in a broad sense that the vast majority<\/em> of supplements on, say, Bryan Johnson’s Blueprint<\/a> are simply not beneficial.<\/p>\n\n\n\n It is important to emphasize here that the cutoff line I have chosen is relatively arbitrary. Certainly one could argue that glycine has some<\/em> effect even when dosed at low levels to humans; one might even argue that the strength of the taurine study is sufficient even despite its lack of replication; one might then move down the list to increasingly unvalidated interventions, etc.<\/em> However, again, from a precautionary perspective, in order to avoid the risk of wasting our time and money and introducing the potential for dangerous drug-drug interactions, I do not personally<\/em> believe that it is worth considering interventions on the basis of model organism data beyond those listed above.<\/p>\n\n\n\n Epidemiological data on coffee consumption<\/strong><\/p>\n\n\n\n Now that we have wrapped up our discussion of interventional data in model organisms, we can move to our second category of potential interventions, namely, treatments which appear to show robust benefits in noncausal human data. Unfortunately, there is no analogous NIA ITP in this setting, and hence no list of specific treatments we can work our way through.<\/p>\n\n\n\n Thankfully, there has been so little validated in this domain that it is quite straightforward to parse. A great deal of studies purporting to identify protective effects of specific foods have turned out to be hopelessly confounded by wealth. For example, red wine was famously believed to be protective against mortality at low levels of consumption; however, this story has been largely disproven at multiple levels:<\/p>\n\n\n\n There is no longer any reason to believe that moderate alcohol consumption extends life or that any component of red wine exerts meaningfully beneficial physiological effects.<\/p>\n\n\n\n There is also much discussion about “Blue Zones” and the Mediterranean or Okinawan diets. Whether or not these diets are in fact good, there are far too many confounding factors (such as varying genetic backgrounds as well as the nonconstant nature of dietary practices over time) to say anything specific or to make precise recommendations, and I do not believe it is valuable to devote excessive attention to the literature in this area, as long as one makes some generic effort to “eat healthy.”<\/p>\n\n\n\n In actuality, I believe there is only one specific item of food (so setting aside nutritional components like fiber) which has met a sufficient standard of evidence that I would consider it somewhat likely to have protective, anti-mortality effects. This item is coffee, which shows a dose-dependent reduction in all-cause mortality across multiple large and well-characterized cohorts of diverse genetic backgrounds:<\/p>\n\n\n\n Only a small sampling of the literature is given above, and the reader may verify that analogous results have been reported for a number of specific health outcomes beyond just all-cause mortality.<\/p>\n\n\n\n Despite efforts to control for socioeconomic background, wealth, ethnicity, weight, dietary composition, and so on, could it nevertheless remain the case that these results remain somehow confounded, and that coffee consumption actually has zero beneficial effect whatsoever? The possibility certainly exists, and in the absence of truly interventional data, it is very difficult to establish certainty about causality. However, given the other benefits of coffee consumption such as mental alertness and the low cost of coffee consumption, it seems prudent to recommend the consumption of 3-4 cups of coffee per day.<\/p>\n\n\n\n The exact mechanism behind coffee’s beneficial effects (to the extent that they exist) is not well understood, especially since caffeine does not seem to be the principal agent of interest here given that mortality risk is also reduced for consumers of decaffeinated coffee. Therefore, it is unclear if, at the margin, the benefits of coffee overlap with those already obtainable via mTORC inhibition or other mechanisms in previously recommended interventions. Curiously, the consumption of unsweetened coffee immediately prior to a meal appears to actually exacerbate<\/em> postprandial spikes in blood glucose (Louie et al.<\/em> (2008)<\/a>), perhaps motivating an approach where one restricts coffee consumption to interludes between mealtimes or in conjunction with an intentionally light breakfast.<\/p>\n\n\n\n Finally, it’s worth noting that residual confounding can influence effect sizes in both directions. Specifically, although coffee consumption seems to have a “U-shaped” dose-response curve with respect to longevity, with all-cause mortality risk seemingly increasing after 4-5 cups of coffee per day, one should consider the possibility that it is so unusual to drink >5 cups of coffee per day that any person who does so is likely subject to abnormal stressors which are inadequately captured in the statistical analysis. Were this to be the case, this could mean that the health benefits of coffee might even be underestimated,<\/em> with the optimal dosage potentially far exceeding 5 cups per day. Of course, we are now well within the realm of pure speculation, but if we are concerned about socioeconomic confounders that lead us to overestimate the benefits of coffee consumption, we may at the very least acknowledge the possibility that confounders in the other direction may very plausibly exist.<\/p>\n\n\n\n Regular blood donation likely has systemic benefits<\/strong><\/p>\n\n\n\n Beyond dietary interventions, one may also wonder what lifestyle habits<\/em> (beyond the obvious ones like exercise) may reduce mortality risk. I believe that frequent blood donation is a compelling candidate here, because it combines weak (but suggestive) cross-sectional data with interventional data in mice and a solid theoretical basis for positive effects.<\/p>\n\n\n\n A study by Ullum et al.<\/em> (2015)<\/a> first suggested that blood donation could exert a pro-longevity effect: controlling for the “healthy donor effect” (where people with better underlying health status are more likely to donate blood), they nevertheless identified a 7.5% reduction in all-cause mortality risk per annual donation in a large cohort of nearly 10 million Scandinavians.<\/p>\n\n\n\n It is, of course, difficult to simply control for what may be deeply pervasive selection effects that elude straightforward quantification, and blood donation carries with it its own risks and adverse effects, ranging from simple skin bruising to temporary dampening of the immune system due to systemic stress. However, two supplemental observations work to considerably strengthen, in my opinion, the rationale behind frequent blood donation.<\/p>\n\n\n\n The first observation is that excessively high iron levels are associated with excess mortality and moderately blocking iron absorption in model organisms is known to prolong longevity (Mangan (2021)<\/a>). While low hemoglobin levels and idiopathic anemia become increasingly prevalent with aging, and individuals should take care to ensure that their iron levels remain above anemic levels, the evidence weakly suggests that the optimal range for longevity is at the lower half of what is typically considered the “normal range.” Indeed, to the extent that consumption of red meat elevates mortality risk, it may partially do so through excessive elevation of iron levels (Etemadi et al.<\/em> (2017)<\/a>). Blood donation, of course, directly removes iron from the body, and preliminary evidence in mice from Liu et al.<\/em> (2022)<\/a> suggests that blood donation ameliorates skin inflammation in old age via clearance of iron deposits.<\/p>\n\n\n\n The second observation, which constitutes a fully independent line of evidence and hence lends substantial marginal credence to the overall thesis of beneficial blood donations, is the study of heterochronic parabiosis in mice, in which the circulatory systems of an old and young mouse are surgically connected. Despite being a deeply invasive and traumatic procedure, considerable physiological benefits and rejuvenation of aged tissues effect have been observed for the older mouse (Conboy et al.<\/em> (2013)<\/a>; Eggel and Wyss-Coray (2014)<\/a>; Ma et al.<\/em> (2022)<\/a>). Originally, it was believed that these benefits came from connecting the circulatory system of the old mouse to the organs of the young mouse, essentially allowing the old mouse to benefit from a set of younger organs; however, work by Rebo et al.<\/em> (2016)<\/a> showed that even a single infusion of old blood exerted severe deleterious effects on a young mouse’s physiology, suggesting that the benefits of heterochronic parabiosis are partially, and perhaps almost entirely, attributable to dilution<\/em> of detrimental inflammatory factors in the circulatory system of the old mouse with “clean\u201c blood from its younger partner. We know that systemic inflammation is a hallmark of aging and that elderly human blood does contain severely elevated levels of a broad range of inflammatory factors, which, when isolated, have almost strictly negative effects, so this model of heterochronic parabiosis is fully consistent with prior understanding, and predicts that blood donation should have a beneficial effect via depletion of undesirable circulating factors.<\/p>\n\n\n\n Because the blood donor population is so heavily selected, it is unclear that we will obtain clear epidemiological evidence on the benefits (or lack thereof) of blood donation in the coming years. However, in this particular case, I believe that the sum totality of the evidence makes the risk-reward profile of regular blood donation at a high frequency (perhaps monthly or bimonthly) quite attractive.<\/p>\n\n\n\n The jury is still out on saunas<\/strong><\/p>\n\n\n\n Beyond blood donation, there has been a slowly growing literature on the benefits of spending more time (up to 3-4 sessions a week) in hot saunas: starting with Laukkanen et al.<\/em> (2015)<\/a> and extending all the way to Kunutsor et al.<\/em> (2022)<\/a> and beyond, a series of papers claim to identify dose-dependent reduction of cardiovascular and all-cause mortality risk attributable to sauna usage. While sauna usage is quite enjoyable, I am skeptical of these claims, and I present them here as an example of the “boundary” of my reasoning about weak epidemiological evidence.<\/p>\n\n\n\n One obvious rejoinder is that these studies are confounded by the fact that regular sauna-goers may be wealthier, exercise harder, ![\"\"](\"https:\/\/milkyeggs.com\/wp-content\/uploads\/2023\/07\/image-2-1024x368.png\")
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